Effect of Orally Active Growth Hormone Secretagogue, MK-677, on Somatic Growth in Rats

Presentation Number: SAT 431
Date of Presentation: April 1st, 2017

Ahreum Kwon*1, Ho-Seong Kim2, Duk Hee Kim3, Hyun-wook Chae1, Mo Kyung Jung1 and Seok Jin Kang1
1Yonsei University College of Medicine, Seoul, Korea, Republic of (South), 2College of Medicine Yonsei University, Seoul, Korea, Republic of (South), 3Sowha Children's Hospital, Seoul, Korea, Republic of (South)

Abstract

Growth hormone secretagogues (GHSs) have been considered as alternative for the treatment of diseases related to growth hormone (GH) deficiency because of their ability to release GH in the body. As GH is a large peptide molecule, it must be injected into subcutaneous tissue or muscle to get it into the blood. However, some types of GHS can effectively stimulate GH release by administration through various routes such as intravenously, subcutaneously, intraperitoneally, and orally. The effects of MK-677, an orally active non-peptide mimic of GHS, on somatic growth were studied in rats. To confirm the GH stimulatory effect of MK-677, the concentration of serum GH was measured at regular intervals after oral administration of 0, 2, or 4 mg MK-677/kg. To investigate the growth-promoting effect of MK-677, body weight and body length were measured after oral administration of 4mg MK-677/kg for 6 weeks. Blood samples were collected from the tail vein every 2 weeks for insulin-like growth factor-I determination. After decapitation, tibia length and epiphyseal plate width were measured, and the pituitary gland and hypothalamus were collected and frozen for analysis of GH, GH releasing hormone, GHS receptor, somatostatin, and somatostatin receptor mRNA by real-time polymerase chain reaction. Oral administration of MK-677 at 4 mg/kg significantly increased peak GH concentrations by 1.8-fold, compared to baseline levels. However, oral administration of MK-677 at 4 mg/kg for 6 weeks did not increase the body length, body weight, width of tibia growth plate, and serum level of insulin-like growth factor-I. At 6 weeks after treatment, the GH response to oral administration of MK-677 was abolished. Pituitary GH mRNA and hypothalamic GHRH mRNA levels did not differ between the control and 6-week treatment groups. Treatment with MK-677 did not alter pituitary and hypothalamic GHSR mRNA expression. Somatostatin mRNA expression in the hypothalamus was markedly increased in the treatment group compare to in controls. In addition, somatostatin receptor-2 mRNA expression in the pituitary gland was decreased in the treatment group compare to the controls. Although oral administration of MK-677 stimulated GH secretion, prolonged administration for 6 weeks attenuated the GH stimulatory effect of MK-677 and did not promote growth, which may be related to increased expression of somatostatin in the hypothalamus. Further studies are needed to overcome the desensitization of growth hormone-releasing peptide after the prolonged clinical treatment of growth disorders.

 

Nothing to Disclose: AK, HSK, DHK, HWC, MKJ, SJK